Diabetes is a chronic metabolic disorder characterized by impaired insulin secretion and/or action. In type 2 diabetes (T2DM), insulin resistance leads to an inability of insulin to control the activity of gluconeogenic enzymes, and many subjects also exhibit inappropriate levels of circulating glucagon (GC) in the fasting and postprandial state. Glucagon is secreted from the α-cells of the pancreatic islets and regulates glucose homeostasis through modulation of hepatic glucose production (Quesada et al., J. Endocrinol. 2008. 199: 5-19).
Glucagon exerts its action on target tissues via the activation of glucocorticoid receptor (GCCR). The glucocorticoid receptor is a 62 kDa protein that is a member of the class B G-protein coupled family of receptors (Brubaker et al., Recept. Channels. 2002. 8: 179-88). GCCR activation leads to signal transduction by G proteins (Gsα and Gq), whereby Gsα activates adenylate cyclase, which causes cAMP production, resulting in an increase in levels of protein kinase A. GCCR signaling in the liver results in increased hepatic glucose production by induction of glycogenolysis and gluconeogenesis along with inhibition of glycogenesis (Jiang and Zhang. Am. J. Physiol. Endocrinol. Metab. 2003. 284: E671-E678). GCCR is also expressed in extrahepatic tissues, which includes heart, intestinal smooth muscle, kidney, brain, and adipose tissue (Hansen et al., Peptides. 1995. 16: 1163-1166).
Development of GCCR inhibitors have been hampered by the unfavorable side effects associated with systemic GCCR inhibition, including activation of the hypothalamic-pituitary adrenal (HPA) axis. Inhibition of GCCR activity in the brain can lead to an increase in circulating adrenocorticotropic hormone due to feedback regulation and a consequent increase in secretion of adrenal steroids (Philibert et al., Front. Horm. Res. 1991. 19: 1-17). This, in turn, can produce a myriad of negative chronic steroid-related side-effects. Other studies have demonstrated that specific inactivation of GCCR resulted in hypoglycemia upon prolonged fasting (Opherk et al., Mol. Endocronol. 2004. 18: 1346-1353).
It has previously been demonstrated in pre-clinical models that administration of GCCR antisense oligonucleotides results in tissue-specific accumulation and reduced GCCR expression in liver and adipose tissue (PCT Pub. No. WO2005/071080; PCT Pub. No. WO2007/035759) without affecting GCCR mRNA levels in the CNS or adrenal glands. Thus, antisense inhibition of GCCR mRNA expression has be shown to improve hyperglycemia and hyperlipidemia without activating the HPA axis. The present invention provides compositions and methods for modulating GCCR expression. Antisense compounds for modulating expression of GCCR are disclosed in the aforementioned published patent applications. However, there remains a need for additional improved compounds. The compounds and treatment methods described herein provide significant advantages over the treatments options currently available for GCCR related disorders.
All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated-by-reference for the portions of the document discussed herein, as well as in their entirety.